Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8451799 | Experimental Cell Research | 2017 | 8 Pages |
Abstract
Deregulation of the bone morphogenetic protein (BMP) pathway has been documented in colorectal cancer (CRC). Previously, we investigated possible associations between urokinase-type plasminogen activator (uPA) deficiency and expression of extracellular constituents of BMP signaling in a newly developed mouse model of inflammation-driven intestinal neoplasmatogenesis, in which chronic colitis and CRC are induced using dextran sodium sulfate (DSS). In this report, we explored the contribution of intracellular components of Smad-mediated BMP signal transduction using the same model. Interestingly, upon DSS treatment, we noticed an overexpression of Runx1/2/3 transcription factors in both wild-type and uPA-deficient mice. Moreover, Runx1 and Runx2 expression levels exhibited an even higher increase in DSS-treated/uPA-deficient mice as compared to DSS-treated/wild-type animals. In all experimental conditions, in situ investigation of Runx-expressing cell types, revealed detection of all three Runx in the immune cells, yet in the DSS-treated/uPA-deficient mice Runx1 and Runx2 were also identified in the preneoplastic epithelium of advanced high-grade dysplasia and carcinoma in-situ colonic lesions. Finally, the uPA-deficient pro-tumorigenic colitic microenvironment exhibited increased levels of the Runx-induced target genes Snai2, Bim and Claudin1, known to have a role in tumor development and progression. These findings suggest that the absence of uPA correlates with increased levels of Runx transcriptional regulators in a way that promotes inflammation-associated carcinogenesis.
Keywords
ECMDextran sodium sulfate (DSS)RunxR-SmadsBone Morphogenetic Proteins (BMP)co-SMADMLNSMADCLDN1uPATGF-βDSSI-SmadsGALTInhibitory SmadsSmurfepithelial to mesenchymal transitionImmunohistochemistryIHCgut-associated lymphoid tissuetransforming growth factor-βEMTColorectal cancerColorectal cancer (CRC)dextran sodium sulfatereceptor-regulated Smadsurokinase-type plasminogen activatorExtracellular matrixMouse modelBMPinhibitor of differentiationBone morphogenetic proteinCRCmesenteric lymph nodes
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Authors
Hara Afaloniati, George S. Karagiannis, Alexandros Hardas, Theofilos Poutahidis, Katerina Angelopoulou,